tbuckley/cabot-search huggingface dataset:
Experimental photodynamic therapy in the treatment of lung tumor.
Authors: Ekaterina Fedorovna Komarova, Marina A. Engibaryan, Yulia V. Ulianova, Viktoriya L. Volkova, Mamuka V. Bauzhadze, Irina V. Pustovaya, Natalia A. Chertova, Elena G. Goncharova, Astanda K. Gvaramiya, Mary L. Maldonado, Maria A. Cherkes, Elizaveta Komarova, Anna S. Goncharova, L. Z. Kurbanova
Journal: Journal of Clinical Oncology (2022)

e20515 Background: Study of the effect of photodynamic therapy (PDT) with Photoditazine using a high-energy laser at various periods after tumor transplantation on the dynamics of growth of experimental Lewis lung carcinoma in mice. Methods: The study included 176 male C57Bl6 mice weighing 18-20 g with Lewis lung carcinoma (LLC) transplanted subcutaneously. The animals received experimental PDT sequential overlapping of fields of influence (662 nm, 3 W, Photoditazine 25 mg/kg, 300 J/cm2). Animals received PDT on day 11 after the transplantation (experimental series I) and on day 21 (experimental series II). Experimental groups were divided in dependence on the exposure area (to the primary tumor -1gr, thorax (area of metastases)-2 gr and to both zones-3 gr). Animals with tumors without PDT were used as controls. Results: PDT with Photoditazine using the 3W laser stimulated the growth of primary tumor node. The degree of stimulation depended on the time of PDT. Increase in tumor sizes differed already on day 7 after PDT at various periods of the LCC growth. During PDT on the 11th day from the moment of tumor inoculation, the percentage of growth on the 7th day after the end of treatment was 60.7; 69.6 and 86.7% in groups 1, 2 and 3, respectively. In the groups of animals that underwent PDT on the 21st day of the growth of the grafted tumor on the 7th day after the end of treatment, the percentage of tumor growth was 20; 35.6 and 24.4% in groups 1, 2 and 3, respectively. Increase in the median survival was registered in experimental animals with PDT on 22.6% compared to control. A smaller increase in tumor volume was observed in animals receiving PDT to the primary tumor, and the group receiving therapy to both areas was in between. Conclusions: The study was shown that with an earlier initiation of PDT, a greater stimulation of tumor growth was revealed than with therapy at a later date. The revealed characteristics of the development of experimental LLC at PDT exposure allows further selection of parameters for photodynamic therapy regimens.
Molecular and immune landscape of <i>FH</i>-mutated cancers.
Authors: Bayan A Al-Share, Sharon Wu, Abdurahman Alloghbi, Samer Alkassis, Anthony Guastella, Anthony Helmstetter, Chadi Nabhan, Bassel Nazha, Pedro C. Barata, Charles J. Ryan, Rana R. McKay, Elisabeth I. Heath
Journal: Journal of Clinical Oncology (2022)

3125 Background: Fumarate Hydratase (FH) encodes an essential enzyme in the TCA cycle. Inactivating germline mutations in FH lead to hereditary leiomyomatosis and renal cell cancer syndrome with risk of development of certain cancers. Sporadic FH mutations have been described in different cancers but implications of somatic mutations on cancer outcomes and survival are not well described. Here, we characterize the molecular landscape of FH-mutant cancers. Methods: Tumors analyzed using NGS (NextSeq, 592 genes; NovaSeq, WES), IHC, and WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 tested by 22c3, 28-8 (Agilent) and SP-142 (Spring Biosciences) IHC (&gt;1%). MSI tested by FA, IHC, and NGS. TMB measured by totaling somatic mutations per tumor (TMB-h &gt; 10 mutations/MB). Real-world overall survival was extracted from insurance claims data and calculated from first treatment to last contact using K-M survival curves for molecularly defined cohorts. Statistical significance was determined using chi-square and Wilcoxon rank-sum test, adjusted for multiple comparisons (q&lt;0.05). Results: 3239 FH mutations were seen in 45 tumor types in 3149 FH-mutated tumors. NSCLC, colorectal and endometrial cancers harbored the most mutations. There were 839 pathogenic (P) or likely pathogenic (LP) and 2400 variants of unknown significance (VUS). Some tumors had multiple mutations. The most common mutations: R233H (P; 37), K477dup (LP; 555), and A41V (VUS; 70). VUS had increased TMB-H (40.4% vs 29.8%, q=0.004) and CREBBP mutations (5.1% vs 1.6%, q=0.012) compared to P+LP. A41V-mt tumors had significantly lower TMB-H than other VUS (8.8% vs 41.5%, q=0.002) and lower MSI-H (3.13% vs 3.69% vs 29.4%, q=0.003) and DICER1, PRKDC, FBXW7 mutations (q&lt;0.05) compared to K477dup and R233. The A41V-mt patients had worse survival compared to patients with P+LP (HR: 1.4, 95% CI: 1.0-2.0, p = 0.049) and a trend toward worse survival compared to K477dup and R233H. In patients treated with chemotherapy, A41 was associated with worse survival compared to P+LP (HR: 4.6, 95% CI: 2.0-10.3, p&lt;0.0001) and compared to K477dup and R233 (p&lt;0.01). There was a trend towards worse survival after IO of A41-mt compared to P+LP (HR: 1.99, 95% CI: 0.88-4.5, p = 0.093). Conclusions: FH alterations are found in multiple cancers. A41V was the most common VUS mutation and is associated with a distinct molecular profile compared to K477dup-mt and R233-mt tumors; it was associated with worse survival in all-comers and after chemotherapy compared to P+LP mutations. This highlights the significance of this mutation and the need for further investigation into how this specific and other FH mutations contribute to cancer progression and treatment outcomes.
Designing a decision aid for cancer prevention.
Authors: Shakira R Milton, Finlay Macrae, Jennifer McIntosh, Sibel Saya, Jon D. Emery
Journal: Journal of Clinical Oncology (2022)

10531 Background: Australian guidelines recommend those aged 50 to 70-years-old without contraindications, consider taking low-dose aspirin (100 mg – 300 mg per day) for at least 2.5 years to reduce their risk of colorectal cancer. To increase uptake of the new guidelines, we hypothesized that a decision aid (DA) would help facilitate a discussion between clinicians and patients about aspirin chemoprevention. We aimed to design a DA with clinician and consumer input including state-of-the-art expected frequency trees (EFTs). We aimed to explore clinicians’ opinions about using EFTs with their patients during consultations and gain consumers feedback on DAs including their understanding and their hypothetical decision to take aspirin or not. Methods: Semi-structured interviews were conducted with relevant clinicians including familial cancer clinic staff (geneticists, oncologists and genetic counsellors), gastroenterologists, pharmacists, and general practitioners (GPs). Focus groups were conducted with consumers in the target age range of the guidelines. DAs were developed through an iterative process. The clinician and focus group interview schedules covered ease of comprehension, design, potential effects on decision making, and approaches to implementation of the DA. Coding was inductive and the focus group interviews were independently coded by two researchers. Themes were developed through consensus between the authors. Final versions of the DAs were proposed to consumers for their final approval after all changes were made. Results: Sixty-four interviews were completed with clinicians between March and October 2019. Twelve consumers, aged 50 to 70 years, participated in two focus groups in February and March 2020. The clinicians agreed that the EFTs would be helpful to facilitate a discussion with patients but suggested including an additional estimate of the effects of aspirin on all-cause mortality. Clinicians agreed that patients would benefit from being shown the EFT in a consultation. The consumers felt favorable about the DA, especially if used with a clinician, and suggested some additional changes to the design and wording to improve ease of comprehension. Conclusions: We have designed a DA using novel approaches to communicate risks and benefits of low dose aspirin for cancer and cardiovascular disease prevention. The DAs are currently being trialled in the SITA trial in general practice to determine its impact on informed decision-making and aspirin uptake.
Combination of oligo-fractionated irradiation with nivolumab can induce immune modulation and replacement of T cell clones in patients with gastric cancer (phase I/II clinical study).
Authors: Koji Kono, Kousaku Mimura, Takashi Ogata, Yuya Yoshimoto, Daisaku Yoshida, Shotaro Nakajima, Hisashi Sato, Nozomu Machida, Takanobu Yamada, Yohei Watanabe, Tomoaki Tamaki, Hirohito Fujikawa, Yasuhiro Inokuchi, Suguru Hayase, Hiroyuki Hanayama, Zenichiro Saze, Hiroyuki Katoh, Takashi Oshima, Yoshiyuki Suzuki, Alessandra Nardin
Journal: Journal of Clinical Oncology (2022)

4027 Background: Although basic, translational and clinical research suggest a possibility of synergistic effect of radiation-induced immunogenic cell death with immune checkpoint inhibitors, the effectiveness of the combination therapy is not fully established. Therefore, we conducted a single-arm, phase 1/2 trial (ClinicalTrials.gov, NCT03453164) in gastric cancer (GC) patients treated with a combination of nivolumab and oligo-fractionated irradiation (22.5 Gy/5 fractions/5 days). Methods: Eligible patients (n = 40) had un-resectable advanced or recurrent GC which progressed after primary and secondary chemotherapy with more than one lesion assessable in diagnostic imaging (one lesion must be ≥2cm). PBMCs from enrolled patients underwent high-dimensional flow cytometry-based, multiplexed MHC multimer analysis using a total of 46 tumor-associated antigens (TAA) and 10 virus epitopes and next-generation sequencing-based repertoire analysis of TCR β-chain. Results: The disease control rate (DCR) for the non-irradiated target as abscopal effect as the primary endpoint was 22.5%, and the DCR for the irradiated lesion was 40.0%. The median survival time was 230 days (157-330 days, 95%CI) and probability of 1-year survival rate was 28.6%. Although most TAA-specific T cells could be tracked longitudinally pre- and post-treatment, some several novel TAA-specific CD8 T cells were detected de novo after irradiation, indicating that potential irradiation-driven antigen spreading. Moreover, irradiation was associated with phenotypical changes of TAA-specific CD8 T cells towards higher expressions of KLRG1, HLA-DR, TIGIT and CD160 and lower expression of CD27 and CD127. Furthermore, the T cell clonality evaluated by the inverted Pielou’s evenness indicated that longer survival patients had more diverse TCR beta repertoire during treatment in comparison to shorter survivors. Also, we confirmed several new sequence-reads after radiation and nivolumab treatment in the top 30 most frequent clonotypes. Conclusions: Taken together, our results suggest that irradiation may induce, through immunogenic cell death, an immune-modulating effect with potential antigen spreading and a more diverse TCR repertoire, ultimately resulting in better survival during combination therapy of radiation with nivolumab. Clinical trial information: NCT03453164.
Image-based detection of <i>FGFR3</i>-fusion in urothelial bladder cancer.
Authors: Nir Peled, Jonathan Zalach, Inbal Gazy, Ido Hayun, Assaf Avinoam, Daniel Nataf, Nurit Paz-Yaacov
Journal: Journal of Clinical Oncology (2022)

3072 Background: Fibroblast growth factor receptor-3 (FGFR3) is a transmembrane protein, somatically altered in a large spectrum of cancer types. Chromosomal rearrangement resulting in FGFR3 gene fusions leads to a constitutively active tyrosine kinase, mediating tumorigenesis. FGFR3-fusion is a prognostic and predictive marker as well as a validated therapeutic target in urothelial bladder cancer. Both FISH and RT-PCR assays can be used for the detection of FGFR3 rearrangements while immunohistochemistry lacks sufficient sensitivity and specificity. In recent years advances in next-generation sequencing improved their ability to detect these alterations in clinical settings. However, systemic screening of these alterations is still expensive, time-consuming, and requires expertise personnel for data analysis and interpretation. In this study, we aimed to develop and validate an alternative machine learning (ML) based method for the detection of FGFR3-fusions directly from routine pathology hematoxylin and eosin (H&amp;E) slides. Methods: A cohort of 388 H&amp;E whole slide images of bladder urothelial carcinoma samples, obtained from the TCGA Research Network ( https://www.cancer.gov/tcga ) was used. Cases were randomly divided into training (n = 238) and testing (n = 150) sets. Advanced Convolutional Neural Network (CNN) was used to generate the FGFR3-fusion classifier on the training set following validation on the testing set. Results: Validation of the FGFR3-fusion classifier was performed on a cohort of 150 cases from 19 different centers, including three positive cases of FGFR3-TACC3 fusions and 147 negative cases. The AI-classifier performance was measured in comparison to the TCGA dataset. The model demonstrated 100% sensitivity and 94% specificity, with an Area Under the Curve (AUC) of 0.96. Conclusions: Herein, we demonstrate a real-time ML-based genomic testing solution for FGFR3-fusion detection in bladder cancer directly from H&amp;E stained slide images. Utilization of such an alternative method can facilitate fast, accurate, and systemic screening of patients if integrated within the routine pathological pipeline supporting targeted therapy treatment for these patients.
Association between body mass index and treatment efficacy with immune checkpoint inhibitor therapy: A retrospective study.
Authors: Hannah Wang, Atif Ali, Lyndsey L Prather, Wendy Du, Nan Chen, Aakash Sheth, Vlad Sandulache, Anita Lyn Sabichi, Daniel Ying Wang, Jan Ole Kemnade
Journal: Journal of Clinical Oncology (2022)

2598 Background: Increased body mass index (BMI) has been associated with improved efficacy of immune checkpoint inhibitor therapy (ICI) in cancer patients. We aimed to retrospectively assess the relationship between patient BMI and response to ICI at two unique health care systems in our institution Methods: We identified patients treated with ICI from 2015-2021 at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC) Cancer Center and Baylor St. Luke’s Medical Center (BSLMC), a private hospital-based cancer center, both academic affiliates of Baylor College of Medicine. Clinical details, including BMI, and treatment efficacy were collected. We defined BMI categories as follows: underweight ( &lt; 18.5), normal weight (18.5-24.9), overweight (25-29.9), and obese (≥30). Progression free survival (PFS), overall survival (OS), and overall response rate (ORR) were the primary end points calculated for treatment efficacy. Survival curves were generated using the Kaplan-Meier method, and intergroup comparisons were performed with log-rank test. Cox regression analysis was used to determine whether BMI at ICI initiation was associated with survival. Chi-square testing was used to determine any association between BMI and ORR. Results: We identified 430 patients treated with ICI, 257 (60%) from BSLMC and 173 (40%) from MEDVAMC. 341 patients (79%) were male and 89 (21%) female. Cancer types included 127 (30%) lung, 49 (11%) kidney, 40 (9.3%) bladder, 38 (8.8%) melanoma, and 38 (8.8%) mesothelioma, 34 (7.9%) head and neck, and 104 (24%) other. 160 (37%) patients had a normal BMI at ICI initiation, 37 (8.6%) underweight, 132 (31%) overweight, and 101 (23%) obese. Mean BMIs of different cancer types were as follows: lung (24.7), kidney (29.2), bladder (26.0), melanoma (29.9), mesothelioma (25.25), head and neck (23.7). 292 (68%) patients were treated with ICI monotherapy. The ORR for patients with normal vs. obese BMIs treated with ICI were 28% and 42%, respectively (p = 0.03). In a subset of patients evaluable for survival (n = 322), patients with an obese BMI had a significantly improved median PFS compared to those with normal BMI (36.4 vs. 23.5 months, respectively, p &lt; 0.0001). Multivariable analysis demonstrated that patients with an obese BMI had significantly improved overall survival compared to patients with a normal BMI (HR 0.64, 95% CI 0.44-0.91, p = 0.014). This relationship was also seen in the subset of patients treated with ICI monotherapy (HR 0.66, 95% CI 0.45-0.95, p = 0.029). This association was noted regardless of health care systems. Conclusions: Increased BMI in cancer patients treated with ICI may predict better treatment efficacy and survival outcomes. More research is needed to define this relationship more clearly.
A phase I trial to evaluate the biologic effect of CBM588 (<i>Clostridium butyricum</i>) in combination with cabozantinib plus nivolumab for patients with metastatic renal cell carcinoma (mRCC).
Authors: Luis A Meza, Jasnoor Malhotra, Zeynep Busra Zengin, Nazli Dizman, Joann Hsu, Neal Shiv Chawla, Alex Chehrazi-Raffle, Ramya Muddasani, Ameish Govindarajan, Daniela V. Castro, Tanya B. Dorff, Yung Lyou, Paul Henry Frankel, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2022)

TPS4606 Background: Combination therapy with the immune checkpoint inhibitor (ICI) nivolumab (nivo) and the tyrosine kinase inhibitor cabozantinib (cabo) is a new standard of care for first line treatment of patients with clear cell mRCC. However, despite the improved clinical benefit obtained with this regimen, a subgroup of patients still presents with progressive disease as best response (Choueiri et al NEJM 2021). There is now evidence supporting the role of the gut microbiome in mediating ICI activity (Routy et al Science 2018) and certain bacterial species, such as Bifidobacterium spp. in predisposing clinical response in patients with mRCC receiving ICIs (Salgia et al Eur Urol 2020). Moreover, recent evidence from a phase I clinical trial suggests that the addition of CBM588, a live probiotic comprised primarily of Clostridium butyricum, can enhance clinical response in patients with mRCC receiving nivolumab plus ipilimumab without incurring added toxicity (Meza et al ASCO, 2021). Herein we present the study design of an ongoing phase I study evaluating the biological effect of CBM588 in combination with cabozantinib plus nivolumab in patients with mRCC. Methods: This is an open label, randomized, single institution phase 1 trial for patients with confirmed mRCC with clear cell, papillary, or sarcomatoid components, who have not received prior systemic therapy for metastatic disease. A total of 30 eligible patient will be randomized 1:2 to receive either cabo/nivo at the standard dose/schedule (40mg PO QD and 480mg IV /4wks, respectively) alone or with CBM588 dosed at 80mg PO bid. The primary objective of the study is to determine the biologic effect of CBM588 with cabo/nivo in the modulation of the gut microbiome. This will be done by assessing the changes in Bifidobacterium spp. abundance and Shannon index (a measure of microbiome diversity) in stool specimens. Stool will be collected for bacteriomic profiling at baseline and after 12 weeks of treatment. Metagenomic sequencing will be performed using previously published methods (Dizman et al Cancer Med 2020). Secondary objectives include determining the effect of CBM588 on (1) clinical efficacy, through overall survival, response rate, and progression-free survival; (2) systemic immunomodulation, through assessment of changes in circulating Tregs, circulating cytokines/chemokines, etc; and (3) toxicities. A two-group t-test with a one-sided type I error of 0.05 will be used to assess the study primary endpoint. Clinical trial information: NCT05122546 .
Baseline tumor genomic and gut microbiota association with clinical outcomes in newly diagnosed glioblastoma (GBM) treated with atezolizumab in combination with temozolomide (TMZ) and radiation.
Authors: Shiao-Pei S. Weathers, Haifeng Zhu, Mark Knafl, Ashish Damania, Carlos Kamiya-Matsuoka, Rebecca A. Harrison, Larry Lyons, Cindy Yun, Walter C. Darbonne, Monica Loghin, Marta Penas-Prado, Nazanin Majd, W. K. Alfred Yung, Barbara Jane O'Brien, Ignacio Ivan Wistuba, Andrew Futreal, Jennifer Ann Wargo, Nadim J. Ajami, Scott Eric Woodman, John Frederick de Groot
Journal: Journal of Clinical Oncology (2022)

2006 Background: Checkpoint inhibitor (CPI) therapy has demonstrated overall limited efficacy in the treatment of GBM. Sixty newly diagnosed GBM patients unselected for MGMT status underwent treatment with concurrent atezolizumab with radiation therapy and TMZ followed by adjuvant atezolizumab and TMZ (NCT03174197). Clinical data has been reported previously. Methods: Genomic (WES with somatic mutation and SCNA determination N = total 42 samples, 33 baseline, 9 TP-2), transcriptomic (RNA seq N = total 72 samples, 54 baseline, 18 TP-2), and metagenomic sequencing of fecal samples (N = total 45 samples, 26 pre samples, 13 post RT samples, six 6m samples) analyses were conducted on pre-treatment samples. Findings were correlated with clinical outcome including OS and PFS. Twenty of the 60 patients underwent re-resection for suspected recurrent disease of which nine patients had WES and RNA seq performed successfully on paired pre and post treatment samples. Results: Somatic mutation, copy number and ploidy profiles were consistent with known aberrations in GBM. An unsupervised molecular network-based stratification of pre-treatment tumor mutations resulted in patients being grouped in 3 clusters with survival difference. Patients with GBM harboring an EGFR aberrancy were associated with a relatively worse mOS following treatment compared to patients with tumors enriched with PTEN alterations, while patients with IDH1 mutations had the longest mOS. Gene set enrichment analysis of gene expression in tumors from patients ( &lt; mOS vs ≥mOS) identified genes associated with lymphocyte activation and immune response in patients with longer survival (p &lt; 0.01) Unsupervised hierarchical clustering of bacterial taxa demonstrated two distinct clusters with significant difference by OS. Survival analysis and Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC) revealed distinct taxa associated with OS ( Ruminococcus spp.) and response to treatment ( Eubacterium spp.), respectively. Conclusions: In this small CPI-treated GBM cohort, WES, SCNA and RNA seq identified pre-treatment tumor features that separated patients by survival. The fecal microbiome observations in our GBM cohort warrants further investigation. Clinical trial information: NCT03174197.